Monique Andersson

Mother-to-child transmission of hepatitis B virus in sub-Saharan Africa: time to act

CITATION: Andersson, M. I. et al. 2015. Mother-to-child transmission of hepatitis B virus in sub-Saharan Africa : time to act. Lancet Global Health, 3(7):e358–e359, doi:10.1016/S2214-109X(15)00056-X.

Screening, characterisation and prevention of Hepatitis B virus (HBV) co-infection in HIV-positive children in South Africa

Background In South Africa, the first HBV vaccine dose is administered at age 6 weeks, leaving a potential window for vertical transmission. Insights into HBV seroprevalence in the vulnerable HIV-infected group are important to drive improvements in surveillance, treatment and prevention. Objectives We set out to implement a screening program for HBV among HIV-infected children and adolescents in Kimberley, South Africa. Our aims were to demonstrate that screening is feasible and sustainable, to establish the prevalence of HBV, to characterise the HBV cases we identified, and to inform discussion about the infant vaccination schedule. Study design We tested all HIV positive children (age 0–16) for Hepatitis B surface antigen (HBsAg), delivering this testing as part of routine state-funded care. We followed up HBsAg-positive cases with an extended panel of HBV serology tests, and HBV DNA viral load quantification. Results Our screening campaign was successfully incorporated into routine out-patient care. Among 625 patients tested, we found five positive for HBsAg (0.8%), of whom three were Hepatitis B e-antigen positive. Two additional children initially tested HBsAg-positive but were negative on repeat testing. Antiviral therapy in the HBsAg children was reviewed and adjusted if required. Conclusions The results testify to the overall success of the HBV vaccine campaign. However, we have demonstrated that ongoing vigilance is required to detect cases and prevent transmission events. Further evaluation of the optimum timing of the first vaccine HBV vaccine dose is required; a vaccine dose at birth could reduce prevalence further.

Hepitopes: A live interactive database of HLA class I epitopes in hepatitis B virus

Increased clinical and scientific scrutiny is being applied to hepatitis B virus (HBV), with focus on the development of new therapeutic approaches, ultimately aiming for cure. Defining the optimum natural CD8+ T cell immune responses that arise in HBV, mediated by HLA class I epitope presentation, may help to inform novel immunotherapeutic strategies. Therefore, we have set out to develop a comprehensive database of these epitopes in HBV, coined ‘Hepitopes’. This undertaking has its foundations in a systematic literature review to identify the sites and sequences of all published class I epitopes in HBV. We also collected information regarding the methods used to define each epitope, and any reported associations between an immune response to this epitope and disease outcome. The results of this search have been collated into a new open-access interactive database that is available at http://www.expmedndm.ox.ac.uk/hepitopes. Over time, we will continue to refine and update this resource, as well as inviting contributions from others in the field to support its development. This unique new database is an important foundation for ongoing investigations into the nature and impact of the CD8+ T cell response to HBV.

A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection - A systematic review

Background: Stigma, poverty, and lack of knowledge present barriers to the diagnosis and treatment of chronic infection, especially in resource-limited settings. Chronic Hepatitis B virus (HBV) infection is frequently asymptomatic, but accounts for a substantial long-term burden of morbidity and mortality. In order to improve the success of diagnostic, treatment and preventive strategies, it is important to recognise, investigate and tackle stigma. We set out to assimilate evidence for the nature and impact of stigma associated with HBV infection, and to suggest ways to tackle this challenge. Methods: We carried out a literature search in PubMed using the search terms ‘hepatitis B’, ‘stigma’ to identify relevant papers published between 2007 and 2017 (inclusive), with a particular focus on Africa. Results: We identified a total of 32 articles, of which only two studies were conducted in Africa. Lack of knowledge of HBV was consistently identified, and in some settings there was no local word to describe HBV infection. There were misconceptions about HBV infection, transmission and treatment. Healthcare workers provided inaccurate information to individuals diagnosed with HBV, and poor understanding resulted in lack of preventive measures. Stigma negatively impacted on help-seeking, screening, disclosure, prevention of transmission, and adherence to treatment, and had potential negative impacts on mental health, wellbeing, employment and relationships. Conclusion: Stigma is a potentially major barrier to the successful implementation of preventive, diagnostic and treatment strategies for HBV infection, and yet we highlight a ‘blind spot’, representing a lack of data and limited recognition of this challenge. There is a need for more research in this area, to identify and evaluate interventions that can be used effectively to tackle stigma, and to inform collaborative efforts between patients, clinical services, policy makers, traditional healers, religious leaders, charity organisations and support groups.

Oxford Screening CSF and Respiratory samples (‘OSCAR’): results of a pilot study to screen clinical samples from a diagnostic microbiology laboratory for viruses using Illumina next generation sequencing

ObjectivesThere is increasing interest in the use of metagenomic (next generation sequencing, NGS) approaches for diagnosis of infection. We undertook a pilot study to screen samples submitted to a diagnostic microbiology laboratory in a UK teaching hospital using Illumina HiSeq. In the short-term, this small dataset provides insights into the virome of human respiratory and cerebrospinal fluid (CSF) samples. In the longer term, assimilating metagenomic data sets of this nature can inform optimization of laboratory and bioinformatic methods, and develop foundations for the interpretation of results in a clinical context. The project underpins a larger ongoing effort to develop NGS pipelines for diagnostic use.Data descriptionOur data comprise a complete metagenomic dataset from 20 independent samples (10 CSF and 10 respiratory) submitted to the clinical microbiology laboratory for a large UK teaching hospital (Oxford University Hospitals NHS Foundation Trust). Sequences have been uploaded to the European Nucleotide Archive and are also presented as Krona plots through which the data can be interactively visualized. In the longer term, further optimization is required to better define sensitivity and specificity of this approach to clinical samples.

Hepatitis C Virus (HCV) diagnosis, epidemiology and access to treatment in a UK cohort

Background As direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment. Methods We performed a retrospective study of HCV infection in a UK teaching hospital to evaluate the performance of different diagnostic laboratory tests, to describe the population with active HCV infection, and to determine the proportion of these individuals who access clinical care. Results Over a total time period of 33 months between 2013 and 2016, we tested 38,510 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag+ and/or HCV RNA+) in 359 (positive rate 0.9%). Our in-house HCV-Ab test had a positive predictive value of 87% when compared to repeat HCV-Ab testing in a regional reference laboratory, highlighting the potential for false positives to arise based on a single round of antibody-based screening. Of those confirmed Ab-positive, 70% were HCV RNA positive. HCV-Ag screening performed well, with 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p<0.0001). Among the 359 cases of infection, the median age was 37 years, 85% were male, and 36% were in prison. Among 250 infections for which genotype was available, HCV genotype-1 (n=110) and genotype-3 (n=111) accounted for the majority. 117/359 (33%) attended a clinic appointment and 48 (13%) had curative treatment defined as sustained virologic response at 12 weeks (SVR12). Conclusions HCV-Ab tests should be interpreted with caution as an indicator of population prevalence of HCV infection, both as a result of the detection of individuals who have cleared infection and due to false positive test results. We demonstrate that active HCV infection is over-represented among men and in the prison population. A minority of patients with a diagnosis of HCV infection access clinical care and therapy; enhanced efforts are required to target diagnosis and providing linkage to clinical care within high risk populations. ABBREVIATIONS DAA Direct Acting Antiviral ELISA Enzyme linked immunosorbent assay HCV Hepatitis C Virus HCV-Ab IgG antibody to Hepatitis C virus HCV-Ag Hepatitis C virus core antigen HCV RNA Hepatitis C ribonucleic acid (viral load) MSM men who have sex with men NAT nucleic acid testing PCR polymerase chain reaction (test for viral load) PPV positive predictive value PWID people who inject drugs SDG Sustainable Development Goals SVR sustained virologic response WHO World Health Organisation

Hepatitis C Virus (HCV) epidemiology, diagnosis and access to treatment in a UK cohort

1 Department of Infec/ous Diseases and Microbiology, John Radcliffe Hospital, Oxford, 2 Department of Paediatrics, Peter Medawar Building for Pathogen Research, Oxford, 3 Department of Hepatology, John Radcliffe Hospital, Oxford, 4 Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, 5 NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK. *These authors contributed jointly to this work

A CROSS-SECTIONAL STUDY OF HEPATITIS B VIRUS INFECTION IN HIV-INFECTED CHILDREN IN WINDHOEK, NAMIBIA

Background Hepatitis B virus (HBV) remains endemic in Africa and an important co-morbidity in the HIV epidemic. The HIV treatment guidelines of the World Health Organisation (WHO) recommend tenofovir−lamivudine (or emtricitabine) as first-line therapy for HIV−HBV co-infection management in children ≥10 years old. However, many children in sub-Saharan Africa are not screened for HBV and may remain on lamivudine monotherapy for many years. This study aimed to characterise HBV infection in HIV-infected children in Namibia. Methods The study included HIV-infected/HBsAg-positive children, exposed to lamivudine monotherapy, attending the Katutura paediatric HIV clinic in Windhoek, Namibia. Dried blood spots and serum samples were collected from participants. Serological investigations were performed using Murex assays. HBV DNA viral load was determined using the automated AmpliPrep/COBAS TaqMan HBV test V2.0. Genotyping and mutation analysis were performed through the NCBI HBV Genotyping tool (www.ncbi.nlm.nih.gov/ projects/genotyping/formpage.cgi) and Geno2Pheno (http:// hbv.geno2pheno.org/index.php). Results To date, 14 children have been enrolled; of whom 14 DBS and 11 serum samples were analysed. HBsAg was detected in 10 children (90%; 10/11); 7 were HBeAg-positive/HBeAb-negative and 3 HBeAg-negative. Among HBeAg-negatives, 1 was HBeAb-negative and 2 were HBeAb-positive. One child was non-reactive for all markers. Of the 14 children, 7(50%) tested HBV DNA-positive. Lamivudine drug-associated resistance variants, together with immune escape mutants in the overlapping surface gene, were identified in these children. Resistance mutation patterns included: rtV173L+rtL180M+rt-M204V (4/7; 57%), rtL80I+rtV173L+rtL180M+rtM204I (1/7; 14%) and rtL180M+rtM204V (2/7; 29%); with the overlapping sE164D and/or sI195M variants. HBV strains belonged to genotype E (6/7, 86%) and genotype D3 (1/7, 14%). Conclusions Half of the children included in this study had detectable HBV DNA and showed lamivudine resistance. Uncontrolled HBV infection is associated with an increased risk of severe liver damage and hepatocellular carcinoma. HBsAg screening of HIV-infected children, using cost-effective point-of-care methods, and treatment with tenofovir should be made more widely available in resource-limited settings.